Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson's disease

Abstract

Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC_0-∞ ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC_0-24 , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC_0-24 , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.

FIGURE 1

The final pharmacokinetic model was a two‐compartment model for apomorphine (CMT = 2 for plasma and CMT = 6 for peripheral) and a one‐compartment model for apomorphine sulfate (CMT = 3). Sublingual administration of apomorphine (CMT = 1) included two transit absorption compartments (CMT = 7 and CMT = 8), and subcutaneous administration of apomorphine (CMT = 4) included two transit compartments (CMT = 9 and CMT = 10). The fraction of the apomorphine sublingual film dose that was swallowed was modeled as a first‐order absorption process (k53) of apomorphine sulfate reaching the systemic circulation from the gastrointestinal tract (CMT = 5). The first‐order absorption rate constants for apomorphine sublingual film transit absorption were k17, k78, and k82, where k17 = k78 = k82. The first‐order absorption rate constants for subcutaneous apomorphine were k49, k9T10, and k10T2, where k49 =  k9T10 = k10T2. The parameter k23 represented the first‐order metabolism of apomorphine to apomorphine sulfate, and k30 was the first‐order elimination of apomorphine sulfate. Finally, k26 was the distribution rate constant for apomorphine moving from the central to tissue compartments, and k62 was the distribution rate constant for apomorphine moving from the tissue to central compartments. Biorsc, bioavailability of apomorphine sublingual film relative to subcutaneous apomorphine; Biosl, fraction of apomorphine sublingual film dose not swallowed; CMT, compartment; F ₁, relative bioavailability of apomorphine sublingual film; F ₄, relative bioavailability of subcutaneous apomorphine; F ₅, fraction of apomorphine sublingual film dose swallowed and absorbed as metabolite; V ₂/F, volume of distribution for apomorphine; V ₃/F, volume of distribution for apomorphine sulfate.

FIGURE 2

Influence of dose covariates on apomorphine (a) C_max and (b) AUC_0–∞ after administration of apomorphine sublingual film based on a typical patient with PD (i.e., 65‐year‐old White man with a body weight of 78 kg who received a 20‐mg dose of apomorphine sublingual film with the film strip positioned drug side down, a contact time under the tongue of 3 min, and who did not receive concomitant antiemetic medication). AUC_0–∞, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; C_max, maximum plasma concentration; PD, Parkinson's disease.

FIGURE 3

Predicted apomorphine exposure after administration of (a) apomorphine sublingual film 30 mg, (b) apomorphine sublingual film 35 mg, (c) subcutaneous apomorphine 5 mg, or (d) subcutaneous apomorphine 6 mg administered every 2 h for a total of 5 doses per day. Solid lines are median; dotted lines are 90% prediction interval.